1. Field of the Invention
This invention relates to novel multibinding compounds (agents) that are muscarinic receptor antagonists, pharmaceutical compositions comprising such compounds, and methods of preparing these compounds. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of diseases mediated by these receptors such as chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.
2. References
The following publications are cited in this application as superscript numbers:                1 Bonner, T. I. et al., Science (Washington D.C.) 1987, 237, 527-532.        2 Goyal, R. K., J. Med., 1989, 321, 1022.        3 Hulme, E. C., et al., Annu. Rev. Pharmacol. Toxicol. 1990, 30, 633.        4 Eglen, R. M. and Hegde, S. S., Drug News Perspect. 1997, 10(8), 462-469.        5 Fisher, A., Invest. Drugs, 1997, 6(10), 1395-1411.        6 Martel, A. M., et al., Drugs Future, 1997, 22(2), 135-137.        7 Graul, A. and Castaner, J., Drugs Future, 1996, 21(11), 1105-1108.        8 Graul, A., et al., Drugs Future, 1997, 22(7), 733-737.        
All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
A receptor is a biological structure with one or more binding domains that reversibly complexes with one or more ligands, where that complexation has biological consequences. Receptors can exist entirely outside the cell (extracellular receptors), within the cell membrane (but presenting sections of the receptor to the extracellular milieu and cytosol), or entirely within the cell (intracellular receptors). They may also function independently of a cell (e.g., clot formation). Receptors within the cell membrane allow a cell to communicate with the space outside of its boundaries (i.e., signaling) as well as to function in the transport of molecules and ions into and out of the cell.
A ligand is a binding partner for a specific receptor or family of receptors. A ligand may be the endogenous ligand for the receptor or alternatively may be a synthetic ligand for the receptor such as a drug, a drug candidate or a pharmacological tool.
The super family of seven transmembrane proteins (7-TMs), also called G-protein coupled receptors (GPCRs), represents one of the most significant classes of membrane bound receptors that communicate changes that occur outside of the cell's boundaries to its interior, triggering a cellular response when appropriate. The G-proteins, when activated, affect a wide range of downstream effector systems both positively and negatively (e.g., ion channels, protein kinase cascades, transcription, transmigration of adhesion proteins, and the like).
Muscarinic receptors are members of the G-protein coupled receptors that are composed of a family of five receptor sub-types (M1, M2, M3, M4 and M5) and are activated by the neurotransmitter acetylcholine1. These receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The regional distribution of these receptor subtypes in the brain and other organs has been documented1-4. For example, the smooth muscle is composed largely of M2 and M3 receptors, cardiac muscle is composed largely of M2 receptors, and salivary glands are largely composed of M3 receptors.
It has been established that the muscarinic receptors are involved in diseases such as chronic obstructive pulmonary disease5-6, asthma, irritable bowel syndrome7, urinary incontinence7-8, rhinitis, spasmodic colitis, chronic cystitis, and alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, and hyper salvation syndromes. Currently, a number of compounds having muscarinic receptor antagonistic activities are being used to treat these diseases. For example, oxybutynin is being used for the treatment of urinary urge incontinence and dicyclomine for the treatment of irritable bowel syndrome. However, these drugs have limited utility as they produce side effects such as dry mouth, blurred vision, and mydriasis. Therefore, there is a need for muscarinic receptor antagonists that will help in the treatment of the above diseases without the adverse side effects.
The multibinding compounds of the present invention fulfill this need.